Prepared by

FATTY LIVER (1) Darien Liew Daojuin

GENERAL PATHOLOGY OF ALD & NAFLD 14 May 2017
OVERVIEW
Fatty liver is the accumulation of triglycerides and other fats in the
liver cells. The amount of fatty acid in the liver depends on the
balance between the processes of delivery and removal.

Pathologic changes observed in patients with fatty liver disease (ALD)

can be divided into the following 3 groups:
Hepatic steatosis
Hepatitis (or steatohepatitis)
Cirrhosis

This lecture aims to cover the pathological basis in both ALD and NAFLD. The next 2
lectures will cover the specifics of ALD and NAFLD respectively.
ALCOHOLIC LIVER DISEASE
Forms of ALD
1. Hepatic steatosis
2. Alcoholic hepatitis
3. Fibrosis
4. Cirrhosis

For some unknown reason, cirrhosis develops in only a small fraction of

chronic alcoholics. All 3 forms can also be features in NAFLD.
NON-ALCOHOLIC FATTY LIVER DISEASE

NAFLD represents a spectrum of Forms of ALD

disorders that have in common the
presence of hepatic steatosis (fatty liver) 1. Hepatic steatosis
in individuals who do not consume 2. Non Alcoholic
alcohol or do so in very small quantities Steaohepatitis (NASH)
(less than 20 g of ethanol/week).
3. Fibrosis
NAFLD is associated with insulin
resistance and metabolic syndrome. 4. Cirrhosis
1. Obesity
2. Type 2 diabetes
3. Dyslipedemia
4. Hypertension
BASIC ANATOMY
ZONAL INJURY
The periportal zone I is nearest to the entering vascular supply and
receives the most oxygenated blood, making it least sensitive to ischemic
injury while making it very susceptible to viral hepatitis.
Conversely, the centrilobular zone III has the poorest oxygenation, and
will be most affected during a time of ischemia.
Functionally, zone I hepatocytes are specialized for oxidative liver
functions such as gluconeogenesis, -oxidation of fatty acids and
cholesterol synthesis, while zone III cells are more important for glycolysis,
lipogenesis and cytochrome P-450-based drug detoxification.
This specialization is reflected histologically; the detoxifying zone III cells
have the highest concentration of CYP2E1 and thus are most sensitive to
NAPQI production in acetaminophen toxicity. Other zonal injury patterns
include zone I deposition of hemosiderin in hemochromatosis and zone II
necrosis in yellow fever.
 PATHOLOGY (1)
STEATOSIS
The pathology of both ALD and NAFLD are interelated and will be explained in the
contexts of ALD.
Hepatic steatosis is defined as intrahepatic fat of at least 5% of liver weight. Simple
accumulation of triacylglycerols in the liver could be hepatoprotective; however,
prolonged hepatic lipid storage may lead to liver metabolic dysfunction, inflammation,
and advanced forms of fatty liver disease.
Hepatocellular fat accumulation typically begins in the centrilobular hepatocytes (acinus
zone 3).
The lipid droplets range from small
(microvesicular) to large
(macrovesicular), the largest filling
and expanding the cell and
displacing the nucleus. As steatosis
becomes more extensive, the lipid
accumulation spreads outward
from the central vein to
hepatocytes in the midlobule and
then the periportal regions.

Macroscopically, the fatty liver with

widespread steatosis is large
(weighing 4 to 6 kg or more), soft,
yellow, and greasy.
 PATHOLOGY (2)
STEATOHEPATITIS
Steatohepatitis is characterized by:

Hepatocyte swelling Single or scattered foci of cells undergo swelling (ballooning) and
and necrosis: necrosis. The swelling results from the accumulation of fat and water, as
well as proteins that are normally exported.
Mallory-Denk bodies Present as clumped, amorphous, eosinophilic material in ballooned
hepatocytes. They are made up of tangled skeins of intermediate
filaments such as keratins 8 and 18 in complex with other proteins such
as ubiquitin. These inclusions are a characteristic but not specific feature
of alcoholic liver disease, since they are also present in non-alcoholic
fatty liver disease and in periportal distributions in Wilson disease and
in chronic biliary tract diseases.
Neutrophilic reaction Neutrophils permeate the hepatic lobule and accumulate around
degenerating hepatocytes, particularly those having Mallory-Denk
bodies. They may be more or less admixed with mononuclear cells
PATHOLOGY (3)
STEATOFIBROSIS

Alcoholic/steato-hepatitis is often accompanied by prominent

activation of sinusoidal stellate cells and portal fibroblasts, giving rise
to fibrosis. Cytokines & chemokines from Kupffer cells stimulate the
hepatic stellate cells (cells of Ito) to form fibrous tissue.
Fibrosis begins with sclerosis of central veins. Perisinusoidal scar then
accumulates in the space of Disse of the centrilobular region,
spreading outward, encircling individual or small clusters of
hepatocytes in a chicken wire fence pattern. These webs of scar
eventually link to portal tracts and then begin to condense into
central-portal fibrous septa.
PATHOLOGY (4)
CIRRHOSIS IN FATTY LIVER

With developing nodularity, cirrhosis becomes established.

With regards to alcohol, prolonged alcohol consumption for a long
period of time, there will be a continual subdivision of established
nodules by new webs of, perisinusoidal scarring leads to a classic
micronodular or Laennec cirrhosis first described for end-stage
alcoholic liver disease.
Early stages of scarring can regress with cessation of alcohol use, but
the farther along toward cirrhosis the liver gets, the more vascular
derangements prevent a full restoration of normal.
Complete regression of alcoholic cirrhosis, while reported, is rare
PATHOLOGY (4)
CIRRHOSIS IN FATTY LIVER
Cirrhosis is a histological diagnosis. It
evolves over years as progressive
fibrosis and widespread hepatocyte
loss lead to distortion of the normal
liver architecture that disrupts the
hepatic vasculature, causing
portosystemic shunts.
Cirrhosis can be classified histologically into:
Micronodular cirrhosis, characterised by small nodules
about 1 mm in diameter and typically seen in alcoholic
cirrhosis.
Macronodular cirrhosis, characterised by larger nodules of
various sizes. Areas of previous collapse of the liver
architecture are evidenced by large fibrous scars.
NALFD
The term nonalcoholic steatohepatitis (or its common acronym NASH) is
often used to denote overt clinical features of liver injury, such as
elevated serum transaminases, but the designation NAFLD is preferred,
with steatohepatitis reserved for histologic features of hepatocyte injury
already described before.
The histologic hallmarks of NAFLD are most consistently associated with
the metabolic syndrome.
NASH almost completely overlaps in its histologic features with alcoholic
hepatitis. In NASH, compared with alcoholic hepatitis, mononuclear cells
may be more prominent than neutrophis and Mallory-Denk bodies are
often less prominent. Steatofibrosis in NAFLD shows precisely the same
features and progression as it does in alcoholic liver disease, although
portal fibrosis may be more prominent.
NALFD
REFERENCES
1. http://www.nature.com/nri/journal/v14/n3/full/nri3623.html
2. http://emedicine.medscape.com/article/175472-overview#a5
3. Robbins Basic Pathology, 9th Edition
4. Robbin and Cotrans Pathologic Basis of Disease, 9th Edition
5. Davidsons Principles and Practice of Medicine, 22nd Edition
6. Kumar and Clarks Clinical Medicine 8th Edition